A. Congestive Heart Failure
Congestive heart failure (CHF) is a serious condition affecting an estimated 5 million Americans. Increasing prevalence, hospitalizations, and deaths have made CHF a major chronic health condition in the United States. There are an estimated 400,000 new cases of CHF each year. These cases are often first diagnosed as the end stage of cardiac disease. The average mortality rate of CHF is 10 percent after the 1st year and 50 percent after 5 years. Thus, half of the patients diagnosed with CHF will die within 5 years of their diagnosis.
The magnitude of the problem is expected to get much worse as more cardiac patients are able to survive and live longer. As patients live longer, the potential for developing CHF increases. In addition, because the incidence of heart failure rises substantially beyond age 65, the prevalence of this condition is likely to increase as the population ages.
The high prevalence of heart failure and the resulting high cost of caring for these patients places a significant economic burden on society. The American Heart Association statistics report that, including medications, an estimated $22.5 billion will be spent for the care of CHF patients in hospitals, physicians offices, home care, and nursing homes including medications in the year 2000. In light of the high costs and poor prognosis of CHF, there is a pressing need to prevent this condition and provide better clinical management to reduce morbidity and mortality.
Congestive heart failure (CHF) is a diseased condition in which the heart fails to function efficiently as a pump to provide sufficient blood flow and/or pressure to fulfill the normal circulatory needs of a patient. CHF results in sudden shortness of breath, fainting and irregular heart beats that require frequent emergency room treatments (acute CHF), and in its chronic form leads to repeated hospital stays, deteriorating quality of life and significant costs to the health care system. Congestive heart failure is characterized by: (1) signs and symptoms of intravascular and interstitial volume overload, including shortness of breath, fluid in the lungs, and edema, and (2) manifestations of inadequate tissue perfusion, such as fatigue or poor exercise tolerance. These signs and symptoms result when the heart is unable to generate a cardiac output sufficient to meet the body's demands.
In CHF, the failing heart is not able to generate sufficient blood pressure to properly perfuse the kidneys, e.g., provide sufficient blood pressure to force blood through the kidneys and filter the blood. In a patient suffering from chronic heart failure, the blood pressure tends to progressively decrease as the heart progressively fails over weeks, months or years. With the decrease in blood pressure there is a concomitant decrease in organ perfusion. Accordingly, chronic heart failure can lead to chronic impaired renal perfusion.
Chronic heart failure patients frequently evolve into acute CHF and are admitted to hospital with an abrupt worsening of their condition. During these periods of acute hypotension (or low blood pressure) their kidneys arc particularly at risk from decreased renal blood flow and may be severely injured. In some cases the blood pressure of these patients can be normal but at the expense of the total shutdown of the blood flow to the kidneys.
B. Relationship of Kidney Failure to CHF
The kidneys are a pair of organs that lie in the back of the abdomen on each side of the vertebral column. They play an important regulatory role in maintaining the homeostatic balance of the body. The kidneys function like a complex chemical filtering plant. They eliminate foreign chemicals from the body, regulate inorganic substances and the extracellular fluid, and function as endocrine glands, secreting hormonal substances like renin and erythropoietin.
The main functions of the kidney are to maintain the water balance of the body and control metabolic homeostasis. The kidneys regulate the amount of fluid in the body by making the urine more or less concentrated, thus either reabsorbing or excreting more fluid, respectively. The kidneys also extract undesirable chemicals and concentrate them in urine, while allowing the reabsorption of other chemicals.
The kidney processes of filtration, reabsorption and fluid regulation take place in the renal nephron of the kidney. Within the nephron the smallest circulatory vessels, capillaries and arterioles, form a glomerulus. The glomerulous is intimately associated with the renal tubules to filter wastes from the blood, remove excess water from the body and produce concentrated urine. The glomerular filtration rate (GFR) is a clinical indicator universally accepted as a measure of the ability of the kidney to remove fluid and solutes. GFR is the summary of the physiologic functions of the kidneys.
The kidneys remove the deleterious metabolic products from the blood, which represents a small portion of the total blood volume. The blood is repeatedly circulated through the kidney several times during each day to remove the required amount of these deleterious metabolic products. In a healthy person, the kidney receives approximately 10% of the cardiac output which is the total body blood flow (about 0.5 liters per minute) which, over the course of a day, amounts to 720 liters per day of blood passing through each kidney. Significantly more blood fluid is filtered through the kidneys than is excreted as urine. Most of the filtered blood fluid must be reabsorbed into the circulatory system to maintain the fluid balance of the body.
Without properly functioning kidneys, a patient will suffer water retention, reduced urine flow and an accumulation of wastes toxins in the blood and body. These conditions resulting from reduced renal function or renal failure (kidney failure) are believed to increase the workload of the heart. In a CHF patient, renal failure because of decreased renal perfusion will cause the heart to further deteriorate. Water and blood toxins accumulate due to the poorly functioning kidneys and in turn, cause the heart further harm.
Fluid overload during CHF is caused in two ways. First, activation of neurohormonal mechanisms of the renin-angiotensin system and aldosterone activation leads to peripheral vasoconstriction and retention of salt, thus water by the kidney. Second, the persistent lower renal blood flow and pressure cannot generate adequate hydrostatic pressure to make sufficient urine to remove excess retained fluid. Accordingly, the kidneys are a principal non-cardiac cause of a progressive fluid overload condition in a patient suffering from CHF.
Patients with CHF can also suffer episodes of acute, severe deterioration caused by abrupt decreases in heart function. These episodes are characterized by rapid reductions in blood pressure and flow, especially to the kidney. Similarly to the chronic state, acutely reduced kidney perfusion can result in a sudden, massive retention of fluid leading to pulmonary edema (fluid in lungs). This acute fluid overload taxes an already overburdened heart and can lead to the severest of complications: acute renal failure and death.
C. Prior Kidney Treatments for CHF
To treat CHF, the physicians must fight the body's attempt to inflict itself harm. Physicians can treat the patient with medications that improve the pumping ability of the heart, increase blood pressure and attempt to reactivate a more normal behavior of the body's control (homeostatic) system. Heart failure patients are put on a strict low sodium diet and their fluid intake is monitored. Some patients are limited to as little as one liter of fluid a day. Diuretics are a class of drugs that combat fluid overload. Diuretics affect the kidney function in such a way that the reabsorption of fluid is suppressed. As a result there is more urine output contrary to neurohormonal commands that the kidney is receiving.
When diet, diuretics, and other treatments can no longer achieve adequate fluid removal with existing kidney function, renal replacement therapies such as hemofiltration or dialysis have been increasingly used as a method of removing fluid in the acute CHF state. Acute heart failure can be treated with the Continuous Renal Replacement Therapy (a.k.a. an artificial kidney or dialysis machine) in the ICU (intensive care unit) of a hospital. A dialysis machine is instrumental in reducing fluid overload and preventing such complications as pulmonary edema. However, the dialysis machine can be harmful to other organs and does not protect the kidney itself from further deterioration from the persistently low blood pressure and poor perfusion caused by vasoconstriction of the renal artery and arterioles (smaller branches). Further, renal replacement therapy may be used to remove fluid but is associated with significant complications. Renal replacement is limited since it may cause further abrupt reductions in blood pressure, actually worsening the heart failure state and further renal dysfunction. Physicians are also reluctant to use replacement therapy in unstable patients because of added risk of hypotension.
Continuous hemofiltration is based on the well-established therapy with an artificial kidney (or renal replacement therapy). Blood is continuously extracted from the body, passed through an artificial kidney machine and then returned back to the body. In this hemofiltration process, some of the undesired chemicals can be extracted from the blood. Most importantly for acute heart failure patients, fluid can be filtered out of the blood stream in a slow controlled infusion while concentrating the blood.
Reversing fluid overload can improve heart function and significantly enhance the clinical status of the CHF patient. While therapies, such as hemofiltration, remove fluid from the patient, they can actually lead to lower blood pressure, further deterioration of the heart and ultimately renal failure requiring the patient to undergo permanent dialysis or kidney transplant.
D. Vasodilators in Heart Failure
Until recent years, the therapy of heart failure was devoted to restoring contractility with cardiac glycosides and relieving congestion and edema with diuretics. The additional use of vasodilating agents has been shown to be valuable where conventional therapy alone has been ineffective. The role of vasodilators as first line agents is now more firmly established.
In a CHF, the reduction in cardiac output causes the peripheral resistance to rise in the vascular system in order to maintain perfusion pressure to vital organs. This compensatory increase in peripheral resistance is mediated by increased sympathetic tone and angiotensin. This compensatory response sets up a vicious circle whereby a lowered cardiac output leads to vasoconstriction, which, in turn, further reduces cardiac output as the heart fails to cope against the increased peripheral resistance. Arterial vasodilators administered to CHF patients lower aortic impedance (afterload) and, thus, reduce the workload of the heart. This results in a reduced ventricular end-diastolic volume, pressure and wall tension. If the blood vessels are dilated the amount of work needed for the heart to pump blood forward is decreased and heart efficiency enhanced. Administering systemic vasodilators either orally or added directly to the bloodstream via a bolus IV injection or drip is beneficial to the CHF patient and particularly important to the kidney function. Vasodilatation of renal blood vessels results in increased renal plasma flow, improved renal function, and reduction of the secretion of renin.
Unfortunately in severe heart failure the conventional treatments using vasodilators is limited. The weakened heart has a reduced ability to pump blood and cannot maintain adequate blood pressure. Since the heart can no longer augment its force of contraction, any increase in vasodilation, while beneficial in reducing the work and preserving the heart, has an adverse effect on vital organ perfusion and survival if prolonged. For example, a disadvantage of the conventional treatment of systemic administration, oral or intravenous, is that vasodilators remain in the bloodstream for a prolonged amount of time (until the vasodilators are metabolized or excreted). In view of the problems associated with prolonged retention only very limited amounts of vasodilators can be given to the patient without a risk of severe complications. Even at low or normal doses, commonly clinically used vasodilating agents (such oral compounds as captopril, enalapril or other known class of dilator such as nitroglycerin or the intravenously administered compound sodium nitroprusside) effect the peripheral circulation of blood to the patient's arms, legs, and other peripheral areas. These vasodilating agents reduce systemic vascular resistance and, with a weakened heart incapable of adequately responding to demand, can cause severe hypotension and circulatory collapse.